Benign prostatic hyperplasia (BPH) is the most common benign neoplasm in American men. The prostate itself is a male accessory sex gland with minimal physiologic use—secretion of an alkaline fluid that becomes part of the semen during ejaculation.¹ Its impact on quality of life, especially in elderly patients, can be quite profound, however. Usually at the crux of the problem is a gradual change in prostate size, which can begin when a man is in his 30s or 40s. The symptoms begin to manifest and become especially troubling in later years. For example, 90% of men between 70 and 90 years of age have significant BPH symptoms.¹

Presentation

Patients who present with lower urinary tract symptoms (LUTS) associated with BPH tend to worsen over time. The growth of prostate tissue causes a mechanical obstruction during the early phase of BPH by decreasing the urethral lumen size. Obstructive symptoms are present, including difficulty initiating urination or having a weak stream. Some patients even push on their bladder to initiate urination. Other symptoms include involuntary postvoid dripping and a sensation of having a full bladder with an inability to void completely.¹

Next, irritative symptoms indicative of the late phase of BPH begin to emerge. Unvoided urine can cause the bladder to become hypersensitive to even small amounts of urine.^2,3 As a result, patients are likely to experience increased frequency. "Toilet mapping" involves patients always locating the nearest bathroom.² Patients also have increased urgency and nocturia and may keep a bedpan in the bedroom. Finally, if patients present with BPH complications—such as hydronephrosis, hematuria, renal insufficiency, or frequent urinary tract infections—they should be referred to a urologist.

The clinician should not assume that symptoms call for a definitive diagnosis of BPH by themselves. Other disease states usually are ruled out first, including prostate cancer, prostatitis, and urinary tract infections.⁴ The digital rectal examination (DRE) and the prostatespecific antigen (PSA) laboratory test are helpful in this regard.

The Symptom Score Index (SSI) questionnaire is a very useful tool to establish a baseline of symptom severity and efficacy of treatment. The tool consists of 7 questions, with increased LUTS represented by an increased score (Table⁵). Mild, moderate, and severe BPH is indicated by scores of 0 to 7, 8 to 19, and 20 or greater, respectively.⁶ Although the questionnaire was designed for patient self-administration, the clinician may need to define terms for better comprehension. Also, the same interviewer should conduct the questionnaire to maintain consistency throughout the patient's therapy.

The designations of mild, moderate, and severe BPH are based on an arbitrary point system and may not necessarily indicate the efficacy of the medication. The degree of increase or decrease in the score from baseline is more reliable. Patients detect a "slight" or "moderate" improvement when the score decreases by 3 to 4 points or 5 to 7 points, respectively.⁴

Treatment Options

The goals of treatment for BPH are to improve symptoms, to halt disease progression, and to prevent complications resulting from untreated or undertreated BPH.⁷ Because quality of life is an important consideration, a patient's choice of therapy should take precedence, once the SSI is completed. Therefore, an appropriate treatment for a patient with mild symptoms and no treatment request would include watchful waiting, annual PSA and DRE monitoring, and lifestyle changes (eg, stopping consumption of coffee or diuretics at bedtime). Patients with moderate-to-severe symptoms should be offered either pharmacologic or surgical intervention.⁶

Of the choices for moderate symptoms, BPH medications usually are preferred, including alpha₁-receptor inhibitors and 5-alpha-reductase inhibitors. alpha₁-receptor inhibitors decrease smooth muscle tone in the prostate tissue, bladder neck, and urethra. This action is quick, compared with that of 5-alpha-reductase inhibitors, thus making them the drugs of choice for patients needing immediate symptom relief.⁸

All of the alpha₁-receptor inhibitors are equally efficacious because they decrease the SSI score by an average of 5 to 7 points, when compared with placebo.² These drugs can be stratified into 3 classes, however, depending on their adverse-event profile, degree of receptor and subreceptor selectivity, and chronology of discovery.

Phenoxybenzamine was the first alpha-receptor inhibitor tried for BPH, but it caused severe cardiovascular adverse effects and is no longer used.

The 2nd-generation alpha₁-receptor inhibitors include doxazosin and terazosin. Because they reduce blood pressure, they are FDA-approved for both hypertension and BPH. Therefore, sitting and standing blood pressure should be checked to determine whether the patient can tolerate doxazosin or terazosin. Also, patients should use them only at bedtime to avoid orthostasis or dizziness.⁹ These effects are more pronounced when one of these drugs is combined with other blood pressure medications.

Finally, these medications must be started at a low dose and titrated upward slowly. A feasible titration schedule would be to start with a 1-or 2-mg dose of either of these medications. The prescriber can double the dose every 2 to 4 weeks until the maximum dose is reached (8 mg and 10 mg for doxazosin and terazosin, respectively), adverse effects occur, or LUTS are alleviated. Onset of symptom relief occurs at 1 to 2 weeks and peaks at 2 to 4 weeks after dose titration.⁶

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) revealed some intriguing results with these medications.¹⁰ The doxazosin arm was discontinued early because that drug had no effect on reducing coronary heart disease or total mortality for patients with hypertension, and there was an 80% increased risk for developing heart failure. Therefore, 2nd-generation alpha₁-receptor inhibitors should not be used as singular therapy for the dual treatment of BPH and hypertension. Additional antihypertensives with doxazosin or terazosin are recommended for patients with both disease states.

The 3rd-generation alpha₁-receptor inhibitors, tamsulosin and alfuzosin, are uroselective because they act on prostate tissue without decreasing blood pressure. Thus, they are not FDA-approved for hypertension. Tamsulosin is available in 0.4-mg doses, and alfuzosin is available in 10-mg doses. Both are dosed once daily, but these drugs should be given after the same meal each day rather than at bedtime. Also, they relieve symptoms more quickly (1 day for onset and 1 week for peak relief), compared with the 2nd-generation alpha₁-receptor inhibitors.⁶ Waiting 2 to 4 weeks after starting these medications to evaluate efficacy ensures a peak response, however. The adverse effects of tamsulosin and alfuzosin include dizziness, asthenia, and, in the case of tamsulosin, abnormal ejaculation.¹¹

The 5-alpha-reductase inhibitors, finasteride and dutasteride, shrink prostate tissue by apoptosis and inhibit the enzyme that converts testosterone to dihydrotestosterone.^12,13 Finasteride and dutasteride are available in 5-and 0.5-mg dosage forms, respectively, and are administered once daily regardless of meals or time of day. Because the mechanism of action relies on shrinking the prostate tissue, symptom relief takes up to 6 months after starting daily use. Also, these medications should be reserved in most cases for patients with enlarged prostates (>40 g), since studies have consistently shown that patients with smaller prostate sizes do not experience significant symptom relief.^12,13 On the positive side, these drugs have been proven to attenuate disease progression, including the need for surgical intervention or the development of acute urinary retention.¹⁴ These 5-alpha-reductase inhibitors are teratogenic. Also, adverse effects include erectile dysfunction, decreased libido, and ejaculatory disorder.

If the maximum titration of an alpha₁-receptor inhibitor does not yield significant relief of LUTS, a 5-alpha-reductase inhibitor may be added. The Medical Therapy of Prostatic Symptoms (MTOPS) trial showed increased efficacy in relief of symptoms and reduction of disease progression when using both classes, compared with either class alone. Adverse effects are significantly increased, however, when using both classes together, and a benefit is most likely for patients with enlarged prostates.¹⁴ Finally, if symptoms are moderate or severe despite maximum use of medications, surgery is an option that should be discussed with a urologist.⁶

A word of caution is needed concerning herbal therapies: although they represent attractive alternatives for men seeking relief from LUTS, they should not be recommended for most patients. Studies comparing herbal versus prescription medications are inhibited by a lack of standardization for symptom scores and the general use of an open label.¹⁵ Clinically, if patients exhibit symptoms severe enough to request relief (ie, moderate-to-severe BPH), they should be offered prescription-strength medication relief rather than herbal therapy.⁶

BPH Management in Primary Care Practice

The patient's need for symptomatic relief, degree of prostate enlargement, and tolerability of the medication should all be considered when using BPH medications. Because 2nd-generation alpha₁-receptor inhibitors can cause significant blood pressure reduction—and this reduction is increased proportional to the dose—these medications should be used for men who can tolerate dose adjustment for full symptom relief. Also, the elderly may be susceptible to falls from the adverse effects of dizziness and syncope. Thus, 3rd-generation alpha₁-receptor inhibitors may be a better choice for patients with baseline hypotension or orthostasis.²

Other factors also contribute to increased LUTS. Stopping or decreasing the dose of certain concomitant medications could alleviate LUTS. For example, nasal decongestants such as pseudoephedrine stimulate prostate alpha receptors, and anticholinergics such as antihistamines and tricyclic antidepressants increase urination frequency. Also, patients who use twice-daily diuretics could combine their daily dose into morning administration only, thus preventing significant nocturia. Finally, clinicians should talk to patients about commonsense measures, such as eliminating water, coffee, and tea consumption after their evening meals.²

Conclusion

The impact of untreated or undertreated LUTS on quality of life is enormous. Thus, this disease state should be treated as thoroughly as other chronic disease states. A baseline SSI can be measured against subsequent scores throughout therapy. By selecting the most appropriate medication therapy and maintaining a vigilant examination on successive patient visits, the clinician can significantly reduce LUTS and considerably improve patients' quality of life.

Dr. Sherman is an associate professor of pharmacy practice at University of Louisiana at Monroe College of Pharmacy.

References

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14.McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:2387-2398.

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